Sexually transmitted diseases (STDs) are among the most prevalent and communicable diseases, and continue to be a significant public health problem. It is estimated that more than 250 million people worldwide, and close to 3 million people in the United States, are infected annually by gonorrhea. Annual worldwide incidence of syphilis is estimated at 50 million people, with 400,000 in the United States annually needing treatment. More recently, the human immunodeficiency virus (HIV), resulting in fatal acquired immunodeficiency syndrome (AIDS), has spread rapidly in both homosexual and heterosexual groups. Strong associations have now also been discovered between cervical cancer and papillomaviruses (PVs). It has been estimated that about 25% of women worldwide have human papillomavirus (HPV) genital infection.
The human papillomaviruses (HPVs), of which there are now more than 90 known types, cause papillomas (warts) in a variety of human epithelial targets including common warts of the hands (verruca vulgaris) and feet (plantar warts), as well as genital warts in vulvar, vaginal, cervical and penile epithelium. Genital warts represent a ubiquitous STD. Women with genital lesions containing certain HPV types, including types 16, 18, 31, 33 and 35, are at increased risk for progression to cervical cancer. In the United States, 15,000 women per year are diagnosed with cervical cancer, and there are about 5000 deaths per year. In developing countries, cervical cancer is the leading cause of cancer related deaths among women.
PVs present a unique challenge for investigators attempting to identify virucidal agents. PVs are inherently extremely resistive to attack by antimicrobial agents. In addition, PVs do not exist free in nature in the same manner that many non-enveloped viruses exist. Rather, PVs exist encased in the squames of differentiated epithelial cells. Thus, the PVs are not only protected by their own very difficult to penetrate capsids, but also by the surrounding, heavily keratinized and cross-linked squames of epithelial cells.
One approach to the general control of STDs is the use of topically applied, female controlled microbicides that inactivate the relevant pathogens. Most frequently, these microbicides are spermicidal preparations containing NONOXYL-9 (N-9) detergent that inactivates enveloped viruses, such as HSV-2 and HIV-1. To date, these preparations have not been effective, however, against non-enveloped viruses such as the HPVs.
Inability to inactivate HPVs makes N-9 an inadequate virucide against this STD. In addition, chronic use of N-9 was recently associated with increased seroconversion for positivity to HIV-1 antibodies in a group of prostitutes, raising the possibility that N-9 may erode vaginal epithelium. Frequent use of N-9 is also positively correlated with bacterial vaginosis, genital ulcers and vulvitis, vaginal candidiasis, toxic shock syndrome, and epithelial disruption of the cervix and the vagina. The detergent, however, is spermicidal and has been shown to inactivate enveloped viruses. It is present in a large number of condoms and other spermicidal agents.
Other microbicides, such as octoxynol-9 (O-9), benzalkonium chloride (BZK) and chlorhexidine, are also surfactants that can disrupt the envelopes of HSV-2 and HIV-1 via surfactant/detergent properties. Like N-9, however, these microbicides also do not inactivate the non-enveloped PVs. Topical microbicides for inactivation of the PVs and prevention of animal or human transmission are currently not available, but would be highly desirable given the ubiquous nature of HPV infections.
U.S. Pat. No. 5,004,757 is directed to a method of deactivating viruses on surfaces by applying a three-part composition containing gluteraldehyde. The composition also contains hydrogen-bonded glycol molecules to eliminate aldehyde odor, and an anionic surfactant such as sodium dodecyl sulfate (SDS) as a potentiator of the virucidal activity of the gluteraldehyde component. The patent indicates that SDS has limited virucidal activity on its own, but has a synergistic effect when combined with gluteraldehyde. Due to the presence of gluteraldehyde, a well-known mutagen, the formulation is not useful against STDs because it cannot be applied to human epithelium.
What is needed are safe and effective microbicides against STDs which extend microbicidal activity to non-enveloped viruses and, in particular, to papillomaviruses.